Neurofilaments are 10 nm thick intermediate filaments that are major cytoskeletal components of neurons. Mammalian neurofilaments are formed of three different polypeptides with molecular weights of 68-75 (P68), 140-170 (P-150) and 180-220 (P200) kilodaltons. Focal accumulations, in neurons, of 10 nm filaments are a commone feature of various neuropathies, especially the toxic neuropathies induced by hexane derivatives, acrylamide and aluminum salts. The dynamics of neurofilament protein synthesis, processing, assembly and degradation are poorly understood. How any or all of these processes are affected in the pathological process is not known. We propose to continue ongoing research to describe the basic steps in the biology of neurofilaments and to learn which of these steps may be critical in the pathogenic process. Our investigations have shown that each of the neurofilament proteins (NFP) arises from a separate biosynthetic event. Preliminary studies indicate the presence of a "soluble" pool of NFP. We propose to continue these studies to determine the degree of polymerization of this "soluble" protein and the relationship between "soluble" and polymerized NFP. We also shall study the time course of incorporation of newly synthesized NFP into both the "soluble" pool and filaments and shall follow labelled neurofilament proteins as they are transported down the axon to determine their stability in the filaments. By appropriate analysis these experiments will provide a description of the state of NFP in the "soluble" pool and in filaments and will demonstrate whether the assembly and disassembly of each of the NFP are independent events. The effects of hexane derivatives, aluminum and other toxic agents on the dynamics of NFP will be assessed to learn how accumulations of 10 nm filaments may be induced by these agents.